A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency

Reuter, Anne L.; Goji, Katsumi; Bingham, Nathan C.; Matsuo, Masafumi; Parker, Keith L.

doi:10.1530/eje-07-0113

Cited by 43 publications

(47 citation statements)

References 31 publications

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“…First, interallelic association with the known p.Gly146Ala polymorphism (rs1110061) may further reduce NR5A1 activity and contribute to more severe phenotypes (WuQiang et al, 2003; Hasegawa et al, 2004; Wada et al, 2006; Reuter et al, 2007; Köhler et al, 2008; Lourenço et al, 2009; Bashamboo et al, 2010a; Paris et al, 2011; Camats et al, 2012). However, two patients in our cohort also bore the p.Gly146Ala variant besides the pathogenic NR5A1 variants, p.Trp302Cys and p.Tyr404*, and their phenotype was not strikingly distinct or more severe.…”

Section: Discussionmentioning

confidence: 99%

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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“…So far, no clear genotype-phenotype correlation could be detected in patients with NR5A1 mutations. However, in patients with severe forms of 46,XY DSD, previously described mutations are mostly missense mutations in the DNA-binding region (including its accessory DNA-binding domain) or in the ligand-binding domain as well as nonsense mutations leading to severe changes of the protein (8,10,16,21,30,31,32,33,36,37,38,39).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development

Tantawy

Mazen

Soliman

et al. 2014

European Journal of Endocrinology

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Objective: Steroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamicpituitary-gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD. Design: Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum. Methods: Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected. Results: Three novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Mü llerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism. Conclusion: We identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5-15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure.

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“…The second mutation was a homozygous missense mutation (R92Q) that disrupts the A-box secondary DNA binding domain [7]. However, recent several studies have demonstrated that heterozygous mutations are more frequently identified in 46, XY disorders of sex development (DSD) patients without adrenal failure rather than in 46, XY DSD patients with adrenal failure [3,[9][10][11][12][13][14][15][16][17]. Therefore, the testis is likely to be more sensitive to partial loss of SF-1/Ad4BP function than the adrenal gland in human.…”

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confidence: 99%

A Novel Heterozygous Mutation of Steroidogenic Factor-1 (SF-1/Ad4BP) Gene (NR5A1) in a 46, XY Disorders of Sex Development (DSD) Patient without Adrenal Failure

2009

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(NR5A1) were identified in two 46, XY female patients with adrenal insufficiency and gonadal dysgenesis [6,7]. The first mutation (G35E) was a heterozygous mutation, which occurred in the P-box of the first zinc finger domain required for the DNA-binding [6,8]. The second mutation was a homozygous missense mutation (R92Q) that disrupts the A-box secondary DNA binding domain [7]. However, recent several studies have demonstrated that heterozygous mutations are more frequently identified in 46, XY disorders of sex development (DSD) patients without adrenal failure rather than in 46, XY DSD patients with adrenal failure [3,[9][10][11][12][13][14][15][16][17]. Therefore, the testis is likely to be more sensitive to partial loss of SF-1/Ad4BP function than the adrenal gland in human. In regard to females with heterozygous NR5A1 mutations, so far seven individuals have been reported [13][14][15][16][17][18]. Among them, only one patient developed adrenal failure, but she had apparently normal ovarian function [18]. The remaining individuals were mothers of 46, XY DSD patients and they did not show any symptoms of adrenal and ovarian failure [13][14][15][16][17]. Indeed, ovarian development during development and at birth is relatively Abstract. Steroidogenic factor-1 [(SF-1/Ad4BP) (mIm184757)] is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, reproduction, and other metabolic functions. Initially, mutations of SF-1/Ad4BP gene (NR5A1) in humans were identified in two 46, XY female patients with adrenal insufficiency and gonadal dysgenesis. However, recent studies have revealed that heterozygous mutations are more frequently found in 46, XY disorders of sex development (DSD) patients without adrenal failure than in 46, XY DSD patients with adrenal failure. We encountered a japanese female patient of 46, XY DSD without adrenal failure and identified a novel mutation (V41G) of NR5A1. Functional analysis revealed that this mutant protein could not activate CYP19 promoter, indicating loss of function. In conclusion, we add a novel mutation of NR5A1 in 46, XY DSD patient without adrenal failure.

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A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency

Cited by 43 publications

References 31 publications

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development

A Novel Heterozygous Mutation of Steroidogenic Factor-1 (SF-1/Ad4BP) Gene (NR5A1) in a 46, XY Disorders of Sex Development (DSD) Patient without Adrenal Failure

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